Both Alzheimer?s disease (AD) and depression have become increasingly more prevalent in the homebound elderly, leading to increased rates of morbidity, nursing home placement and mortality, than what are found in the general elderly population. Our cross-sectional study of an established homebound population in the Boston area has found that low plasma amyloid-a42 (Aa42) is associated with depression independently of cardiovascular disease. We further found that depression with low Aa42 combined with high Aa42 in plasma is associated with poor memory. Similarly other research studies have shown that a high plasma Aa40/Aa42 ratio significantly increased the risk of AD. Multiple studies demonstrate that plasma Aa correlates with cerebral spinal fluid (CSF) Aa when cognition is normal, but this equilibrium disappears after the AD cognitive symptoms occur. We hypothesize the existence of a potential depression subtype associated with Ab peptides in plasma, which we have termed ?amyloid-associated depression?. The purpose of this R01 application is to validate the existence of amyloid-associated depression defined by a high plasma Aa40/Aa42 ratio, and to investigate whether this depression subtype is a prodromal depression of AD. The proposal is based on our established population, and has two aims: Aim 1 is to document memory decline prospectively in those with amyloid-associated depression vs. those with non-amyloid depression vs. the controls. Aim 2 is to investigate the relationship between plasma Aa and CSF Aa, a central nervous system (CNS) biomarker of AD, in the different depression subgroups. Our long-term goal is to identify prodromal signs of AD to help facilitate early treatment of the disease in the homebound elderly population. PUBLIC HEALTH RELEVANCE: The proposed longitudinal study seeks to validate amyloid associated depression by investigating whether the combination of depression and a high plasma Aa40/Aa42 ratio will lead to greater risk of cognitive decline and the finding of the AD biomarkers in CSF as compared to those with a low plasma Aa40/Aa42 ratio or those without depression.